Neuroblastoma is a rare childhood cancer that develops in nerve tissue, often with aggressive progression.
Neuroblastoma is a solid tumor that affects children, with high-risk cases having a poor prognosis. Decades ago, researchers discovered that adding retinoic acid to neuroblastoma treatment improved survival rates by 10-15%, but only during post-chemotherapy consolidation, after the primary tumor had been largely eliminated. For nearly 50 years, the reason behind retinoic acid’s effectiveness in this setting—but not against primary tumors—remained unclear. ()
Now, scientists at St. Jude Children’s Research Hospital have solved the mystery. Their new study, published in Nature Communications, reveals that retinoic acid employs a novel mechanism to eliminate metastasized neuroblastoma by “hijacking” a normal developmental pathway to trigger cancer cell death. These findings could pave the way for new combination therapy strategies.
Decades-Long Mystery of Retinoic Acid’s Effectiveness in Neuroblastoma Solved
“We’ve come up with an explanation for a decades-long contradiction about why retinoic acid works in post-chemotherapy consolidation but has little impact on primary neuroblastoma tumors,” said senior co-corresponding author Paul Geeleher, PhD, St. Jude Department of Computational Biology. “Retinoic acid’s activity heavily depends on the cellular microenvironment.”
The cellular microenvironment is the soup of chemicals, proteins and other signals that surround a cell, and which is unique to that part of the body. For example, the bone marrow microenvironment contains signals to grow blood cells and restructure bone. Metastasized neuroblastoma cells often migrate to bone marrow, where the bone morphogenetic protein (BMP) pathway signaling is highly active. The researchers showed that BMP signaling makes neuroblastoma cells much more vulnerable to retinoic acid.
“Unexpectedly, we found that cells expressing genes from the BMP signaling pathway were very sensitive to retinoic acid,” said co-first and co-corresponding author Min Pan, PhD, St. Jude Department of Computational Biology. “However, since the bone marrow microenvironment causes neuroblastoma cells there to have higher BMP activity, it neatly explained why retinoic acid is very effective at treating those cells during consolidation therapy, but not the primary tumors during up-front treatment.”
Using gene editing technology, the scientists uncovered the relationship between BMP signaling and retinoic acid. They assembled a group of neuroblastoma cell lines susceptible to retinoic acid, then cut out genes to find which were responsible for the drug’s activity. Genes in the BMP pathway had the largest effect while providing a plausible explanation for retinoic acid’s varying outcomes in patients.
“We found that, in neuroblastoma, BMP signaling works with retinoic acid signaling in the same way as during development,” said co-first author Yinwen Zhang, PhD, St. Jude Department of Computational Biology. Zhang characterized how transcription factors, the proteins that bind DNA to regulate gene expression, led to different results in highly retinoic acid-sensitive or insensitive neuroblastoma cells. “If there are a lot of BMP-signaling pathway transcription factors already on DNA, then retinoic acid signaling combines with it to promote downstream cell death–related gene expression. This occurs both in normal embryonic development and neuroblastoma cells in certain microenvironments.”
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“We are the first to uncover such an example of ‘hijacking’ a normal embryonic developmental process preserved in cancer that we can exploit therapeutically,” Geeleher said. “Now, we can look for similar processes in other diseases to design less toxic and more effective treatment strategies.”
Reference:
- Bone morphogenetic protein (BMP) signaling determines neuroblastoma cell fate and sensitivity to retinoic acid – (https://www.nature.com/articles/s41467-025-57185-y)
Source-Eurekalert